Tristetraprolin attenuates schistosomiasis-induced liver fibrosis through m⁶A-mediated regulation of TGF-β1 mRNA stability.

内容摘要

Inhibiting the activation of hepatic stellate cells (HSCs) represents a key therapeutic strategy for alleviating liver fibrosis induced by schistosomiasis. Diverse cell populations secrete pro-inflammatory cytokines and chemokines, which induce HSC activation and thereby promote hepatic fibrosis progression. Tristetraprolin (TTP) exerts a pivotal role in the post-transcriptional regulation of pro-inflammatory cytokines by either accelerating mRNA degradation or suppressing translation, a regulatory mechanism closely associated with the pathogenesis of various hepatic disorders. However, the pathological roles of TTP in Schistosoma japonicum-induced liver fibrosis remain largely elusive. Here, we report that TTP is upregulated in the liver during S. japonicum-induced liver fibrosis, and its overexpression markedly ameliorates this fibrotic pathology in vivo. We further identify that TTP negatively regulates TGF-β1 mRNA stability by promoting N6-methyladenosine (m6A) RNA methylation, thereby inhibiting HSC activation. Mechanistically, TTP enhances transcription of the WT1-associated protein (WTAP) gene through its interaction with SMAD2/3. Furthermore, treatment with an m6A RNA methylation inhibitor confirms that TTP-mediated protection against S. japonicum-induced liver fibrosis, an effect associated with increased m⁶A RNA methylation in vivo. Thus, our findings uncover a novel and critical role of TTP in exerting its anti-fibrotic function via the WTAP/m6A epitranscriptomic machinery in the pathogenesis of S. japonicum-induced liver fibrosis. This finding provides a rationale for the therapeutic targeting of TTP-mediated m6A RNA methylation in S. japonicum-induced liver fibrosis.